Prophylactic or therapeutic drug for renal diseases

ABSTRACT

This invention relates to prophylactic or therapeutic drug for diabetic nephropathy or glomerulonephritis, comprising, as an active ingredient, a compound or salt thereof represented by general fornula (I)  
                 
 
     wherein R 1  stands for H or an optionally substituted hydrocarbon residue; R 2  stands for an optionally esterifled carboxyl group; R 3  stands for a group actually or potentially capable of forming an anion; X shows that the phenylene and phenyl groups bind to each other directly or through a spacer having an atomic chain length of two or less; n stands for 1 or 2; ring A stands for a benzene ring having an optional substituent in addition to R 2 ; Y stands for a bond, —O—, —S(O) m — (wherein m stands for 0, 1 or 2), or —N(R 4 )— (wherein R 4  stands for H or an optionally substituted alkyl group).

FIELD OF THE INVENTION

[0001] This invention relates to a prophylactic or therapeutic drugcontaining an angiotensin II antagonistic compound or salt thereof asthe active constituent, for diabetic nephropathy or glomerulonephritis.

BACKGROUND OF THE INVENTION

[0002] The kidneys are a major target organ of hypertension. Prolongedhypertension inducesvarious renal impairments, mainly throughrenovascular lesions. Among them, contraction of renal vessels anddegenerative lesions of elastic fibers lead to further elevation of theblood pressure. It is generally believed that hypertension raises renalintraglomerular pressure, which overloads the glomeruli, stimulatingfibrosis and enlargement of the mesangial region, which advances tohardening of the glomeruli. In diabetic nephropathy as well, elevationin intraglomerular pressure is followed by trace albuminuria,progressing to the sclerosis of the glomeruli. Eventually, renalfunctions decline, resulting in chronic renal failure requiringartificial dialysis therapy. In recent years, 20% of patients withend-stage renal failure who commence artificial dialysis have diabeticnephropathy as the underlying disease. The number of patients likely toreceive artificial dialysis tends to increase year after year, posing acritical problem in the medical care system. At present, it is said thatthere are few ideal pharmaceutical therapies for chronic renal failure,and even that blood-pressure-lowering therapy may aggravate rather thanimprove renal failure.

[0003] Angiotensin II antagonistic compounds are known as a therapeuticdrug for cardiovascular diseases, e.g., hypertension, cardiac diseases(heart enlargement, heart failure, myocardial infarction, etc.),apoplexy, nephritis, etc. (European Patent Official Gazette (EPO)459136A). The mechanism of their action is considered to be based oninhibition of binding to the angiotensin II receptor of angiotensin II,which possesses intense vasoconstrictive action. EP 459136A₁ describesthe availability of angiotensin II antagonists in the treatment ofnephropathy or nephritis.

[0004] Many data of clinical and experimental studies have been reportedon the relation between renal diseases and hypertension. It is nowestablished that the kidneys are directly or indirectly involved in theonset of hypertension, and also are apt to be affected by hypertension.However, hypertension in chronic glomerulonephritis has been poorlyelucidated, particularly as to causative factors, effects ofhypertension on the course of nephritis, and prophylactic effects ofblood pressure lowering therapy.

[0005] Currently, nephritis is considered to be a clinical picture ofdifferent diseases with different entities. In accordance with thepopularization of renal biopsy, renal diseases have been reviewed,resulting in their redefinition as a wide range of diseasescharacterized by proteinuria (“Shibata's Internal Medicine of theKidneys,” by Seiichi Shibata, Bunkodo, 1988). Glomerulonephinis, onceregarded as a single disease, has been differentiated intoglomerulonephritis, chronic pyelonephritis, IgA nephropathy,periarteritis nodosa, gout, diabetes, systemic lupus erythematosus(SLE), hepatic infarction, hereditary renal disease, amyloidosis, andWegener's sarcoma.

[0006] Diabetes associated with hypertension facilitates cardiovascularimpairment and/or other organ complications, greatly affecting lifeexpectancy. Accordingly, it is important to control blood pressurewithin the normal range during treatment, along with the control ofdiabetes and the improvement or prevention of arteriosclerosis.

OBJECT OF THE INVENTION

[0007] This invention provides a prophylactic or therapeutic drug fordiabetic nephropathy or glomerular nephritis.

SUMMARY OF THE INVENTION

[0008] Under the above-mentioned circumstances, the inventorsintensively studied to develop a drug for the prophylaxis or treatmentof nephropathy or nephritis. Ultimately, they found that compoundspossessing angiotensin II antagonistic action, represented by aparticular structural formula, are very effective in the prophylaxis ortreatment of diabetic nephropathy or glomerulonephritis. The presentinvention was thus accomplished.

[0009] Namely, this invention relates to a prophylactic or therapeuticdrug for diabetic nephropathy or glomerulonephritis, containing, as theactive constituent, a compound or salt thereof represented by formula(I):

[0010] (wherein R¹ stands for H or an optionally substituted hydrocarbonresidue; R² stands for an optionally esterified carboxyl group; R³stands for a group actually or potentially capable of forming an anion;X shows that the phenylene and phenyl groups bind to each other directlyor through a spacer having an atomic chain length of two or less; nstands for 1 or 2; ring A stands for a benzene ring having one or twooptional substituents in addition to R²; Y stands for a bond, —O—,—S(O)_(m)— (wherein m stands for 0, 1 or 2), or —N(R⁴)— (wherein R⁴stands for H or an optionally substituted alkyl group)).

DETAILED DESCRIPTION OF Hl INVENTION

[0011] The invented compounds used for prophylactic or therapeuticpurposes, as represented by formula (I), are structurally veryprominently characterized by the coexistence of R², standing for anoptionally esterified carboxyl group, and R³, standing for a groupactually or potentially capable of forming an anion. This structuralcharacteristic contributes to the onset of very intense prophylactic ortherapeutic effect on diabetic nephropathy or glomerulonephritis.

[0012] The compounds of this invention, possessing angiotensin IIantagonistic action, represented by formula (I), can be favorably usedin the prophylaxis or treatment of diabetic nephropathy orglomerulonephritis.

[0013] In formula (I), RI stands for H or an optionally substitutedhydrocarbon residue.

[0014] Examples of the hydrocarbon residue represented by RI includealkyl, alkenyl, alkynyl, cycloalkyl, aryl and aralkyl groups. Among themalkyl, alkenyl and cycloalkyl groups are preferable.

[0015] The alkyl group represented by R¹ is a straight chain or branchedlower alkyl group having 1 to about 8 carbon atoms, as exemplified bymethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl,pentyl, i-pentyl, hexyl, heptyl or octyl.

[0016] The alkenyl group represented by R¹ is a straight chain orbranched lower alkenyl group having 2 to about 8 carbon atoms, asexemplified by vinyl, propenyl, 2-butenyl, 3-butenyl, isobutenyl or2-octenyl.

[0017] The alkynyl group represented by R¹ is a straight chain orbranched lower alkynyl group having 2 to about 8 carbon atoms, asexemplified by ethynyl, 2-propinyl, 2-butynyl, 2-pentynyl or 2-octynyl.

[0018] The cycloalkyl group represented by R¹ is a lower cycloalkylgroup having 3 to about 6 carbon atoms, as exemplified by cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl.

[0019] The above mentioned alkyl, alkenyl, alkynyl or cycloalkyl groupmay optionally be substituted with hydroxyl group, an optionallysubstituted amino group (e.g. amino, N-lower (C14) alkylamino orN,N-dilower (C14) alkylamino), halogen, a lower (C14) alkoxy group, alower (Ci4) alkylthio group.

[0020] The aralkyl group represented by R¹ is, for example, aphenyl-lower (C₁₋₄) alkyl such as benzyl or phenethyl, and the arylgroup represented by Ri is, for example, phenyl.

[0021] The above mentioned aralkyl or aryl group may optionally have, onany position of its benzene ring, for example, halogen (e.g. F, Cl orBr), nitro, an optionally substituted amino group (e.g. amino, N-lower(C₁₋₄) alkylaino or N,N-dilower (C₁₋₄) alkylamino), lower (C1-4) alkoxy(e.g. methoxy or ethoxy), lower (C₁₋₄) alkylthio (e.g. methylthio orethylthio) or lower (C₁₋₄) alkyl (e.g. methyl or ethyl).

[0022] Among the above mentioned groups represented by R¹, optionallysubstituted alkyl, alkenyl or cycloalkyl groups (e.g. a lower (C₁₋₅)alkyl, lower (C2-5) alkenyl or lower (C3-6) cycloalkyl group optionallysubstituted with hydroxyl group, amino group, halogen or a lower (C1-4)alkoxy group) are preferable.

[0023] Y stands for a bond, —O—, —S(O)_(m)(wherein m is 0, 1 or 2) or—N(R⁴)— (wherein R⁴ is hydrogen or an optionally substituted lower alkylgroup). Y is preferably a bond, —O—, —S— or —N(R⁴)— (wherein R⁴ ishydrogen or a lower (C₁₋₄) alkyl group (e.g. methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, t-butyl)).

[0024] With respect to formula (I) above, the group for R³, capable offorming an anion (a group having a hydrogen atom capable of leaving as aproton), or a group capable of changing thereto, is exemplified by 5- to7-membered (preferably 5- or 6-membered) monocyclic heterocyclic ringresidues which contain one or more of N, S and O and which may besubstituted (preferably N-containing heterocyclic residues having ahydrogen atom capable of leaving as a proton), and groups capable ofchanging thereto in vivo. Such groups include the following:

[0025] The chemical bond between the group for R¹³ and the partnerphenyl group may be a carbon-carbon bond as shown above, or anitrogen-carbon bond via one of the several nitrogen atoms when thesymbol g stands for —NH— in the above formulas. For instance,

[0026] when R³ is represented by

[0027] embodiments are

[0028] Other R³ examples binding through the nitrogen atom are

[0029] In the above groups, g stands for —CH₂—, —NR⁷-, oxygen atom, or

[0030] each stand for a carbonyl group, a thiocarbonyl group or anoptionally oxidized sulfur atom (e.g., S, S(O), S(O)₂) (preferably, acarbonyl or thiocarbonyl group; more preferably, a carbonyl group); mstands for the integer 0, 1 or 2; R⁷ stands for a hydrogen atom or anoptionally substituted lower alkyl group (e.g. a lower (C₁₋₄) alkylgroup (e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,t-butyl)).

[0031] Preferable examples of R³ include2,5dihydro-5-oxo-1,2,4oxadiazole ring residue,2,5-dihydro-5-thioxo-1,2,4oxadiazole ring residue or2,5-dihydro-5-oxo-1,2,4thiadiazole ring residue having —NH or —OH groupas proton donor and carbonyl group, thiocarbonyl group or sulfinyl groupas proton acceptor simulateneously.

[0032] And, while the heterocyclic residue represented by R³ may form acondensed ring by connecting the substituents on the ring, it ispreferably a 5-to, 6-membered ring, more preferably a 5-memberedheterocyclic residue. Expecially, groups represented by the formula

[0033] wherein i stands for —O— or —S—; j stands for >C═O, >C═S or>S(O)_(m); m stands for the integer 0, 1 or 2 (in particular,2,5-dihydro-5-oxo-1,2,4-oxadiazole-3-yl;2,5-dihydro-5-thioxo-1,2,4-oxadiazole-3-yl;2,5-dihydro-5-oxo-1,2,4-thiadiazole-3-yl) are preferable. R³ can besubstituted at the ortho, meta or para position, most preferably at theortho position.

[0034] In addition, the above-mentioned heterocyclic residue (R³) havethe following tautomeric isomers:

[0035] In

[0036] when Z=0, and g=0

[0037] the three tautomeric isomers a, b and c exist.

[0038] The heterocyclic residue represented by the above formulacomprises all of these a, b and c.

[0039] Moreover, R³ may be a carboxyl group, tetrazolyl group,trifluoromethanesulfonamide group (—NHSO₂CF₃), phosphate group, sulfonicgroup, cyano group, or lower (C₁₋₄) alkoxycarbonyl group; these groupseach may be protected by an optionally substituted lower alkyl oracylgroup. Any group capable of forming an anion biologically orphysiologically (e.g. through biological reactions such as oxidation,reduction or hydrolysis caused by enzymes in the body) or chemically, ora group capable of changing thereto is acceptable.

[0040] As R³, a tetrazolyl or carboxyl (preferably tetrazolyl) groupoptionally protected by an optionally substituted lower (C₁₋₄) alkyl(e.g., methyl, triphenylmethyl, methoxymethyl, ethoxymethyl,p-methoxybenzyl, p-nitrobenzyl, etc.) or acyl (e.g., lower (C₂₋₅)alkanoyl, benzoyl, etc.) group is preferable. R³ can be replaced at theortho, meta or para position, most preferably at the ortho position.

[0041] X stands for a covalent bond between the 2 phenyl rings or aspacer having a chain length of 1 to 2 atoms as the linear moietybetween the adjoining phenylene group and phenyl group. Preferably, X isa covalent bond. The spacer having a chain length of 1 to 2 atoms mayconsist of a divalent chain in which the number of atoms composing thestraight chain portion is either 1 or 2, and may have a side chain. Forexample, a lower (C₁₋₄) alkylene, —CO—, —O—, —S—, —NH—, —CO—NH—,—O—CH₂—, —S—CH₂—, —CH═CH—, etc. are listed.

[0042] n stands for the integer 1 or 2 (preferably 1).

[0043] The formula represented by the above-mentioned R³, X and n:

[0044] is preferably represented by the formula:

[0045] R² in formula (I) is an optionally esterified carboxyl group.

[0046] The optionally esterified carboxyl group as R² includes the grouprepresented by the formula —CO-D [wherein D stands for a hydroxyl, groupor an optionally substituted alkoxyl group {e.g., a lower (C₁₋₆) alkoxylgroup whose alkyl portion is optionally substituted with a hydroxyl,optionally substituted anmino (e.g., amino, dimethylamino, diethylamino,piperidino, molphorino, etc.), halogen, lower (Clr) alkoxyl, lower (CI6)alkylthio or optionally substituted dioxolanyl (e.g.,5-methyl-2-oxo-1,3-dioxolane-4yl, etc.) group, or the group representedby the formula —O—CH(R⁶)—OCOR⁵ [wherein R⁶ stands for H, a lower (C₁₋₆)straight chain or branched alkyl group (e.g., methyl, ethyR, n-propyl,isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl neopentyl,etc.), a lower (C₁₋₆) straight chain or branched alkenyl group or alower (C₃₋₈) cycloalkyl group (e.g., cyclopentyl, cyclohexyl,cycloheptyl, etc.); R⁵ stands for a lower (C₁₋₆) straight chain orbranched alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, etc.), alower (C₁₋₆) straight chain or branched alkenyl group, a lower (C₃₋₈)cycloalkyl group (e.g., cyclopentyl, cyclohexyl, cycloheptyl, etc.), alower (C₁₋₃) alkyl group substituted with C₃₋₈ cycloalkyl (e.g.cyclopentyl, cyclohexyl, cycloheptyl) or an optionally substituted arylgroup such as phenyl group (e.g., benzyl, p-chlorobenzyl, phenetyl,cyclopentylmethyl, cyclohexylmethyl, etc.), a lower (C₂₋₃) alkenyl groupoptionally substituted with C₃₋₈ cycloalkyl or an optionally substitutedaryl group such as phenyl (e.g., cinnamyl, etc. having alkenyl moietysuch as vinyl, propenyl, allyl and isopropenyl, etc.), an aryl groupsuch as optionally substituted phenyl (e.g., phenyl, p-tolyl, naphtyl,etc.), a lower (C₁₋₆) straight chain or branched alkoxyl group (e.g.,methoxyl, ethoxyl, n-propoxyl, isopropoxyl, n-butoxyl, isobutoxyl,sec-butoxyl, t-butoxyl, n-pentyloxyl, isopentyloxyl, neopentyloxyl,etc.), a lower (C₂₋₈) straight chain or branched alkenyloxyl group(e.g., allyloxyl, isobutenyloxyl, etc.), a lower (C₃₋₈) cycloalkyloxylgroup (e.g., cyclopentyloxyl, cyclohexyloxyl, cycloheptyloxyl, etc.), alower (C₁₋₃) alkoxyl group substituted with a C₃₋₈ cycloalkyl (e.g.,cyclopentyl, cyclohexyl, cycloheptyl, etc.) or an aryl group such asoptionally substituted phenyl (e.g., benzyloxy, phenethyloxy,cyclopentylmethyloxy and cyclohexylmethyloxy having alkoxy moiety suchas methoxy, ethoxy, n-propoxy and isopropoxy), a lower (C₂₋₃) loweralkenyloxy group substituted with a C₃₋₈ cycloalkyl (e.g., cyclopentyl,cyclohexyl, cycloheptyl, etc.) or an optionally substituted aryl groupsuch as phenyl group (e.g., cinnanmyloxy etc. having alkenyloxy moietysuch as vinyloxy, propenyloxy, allyloxy, isopropenyloxy, etc.), or anoptionally substituted aryloxyl group such as phenoxyl (e.g., phenoxyl,p-nitrophenoxyl, naphtoxyl, etc.,)}]. The substituent for R² may be agroup actually or potentially capable of forming an anion (e.g.,tetrazolyl group, trifluoromethanesulfonamide group, phosphate group orsulfonic group optionally protected by an alkyl {e.g., lower (C₁₋₄)alkyl, etc.} or acyl {e.g., lower (C₂₋₅) alkanoyl, optionallysubstituted benzoyl, etc.} group].

[0047] For example, the folowing substituents are listed: —COOH and itssalts, —COOMe, —COOEt, —COOtBu, —COOPr, pivaloyloxymethoxycarbonyl,1-(cyclohexyloxycarbonyloxy)ethoxycarbonyl,(5-methyl-2-oxo-l,3-dioxolane-4-yl)methoxycarbonyl,acetoxymethoxycarbonyl, propionyloxymethoxycarbonyl,n-butylyloxymethoxycarbonyl, isobutylyloxymethoxycarbonyl,1-(ethoxycarbonyloxy)ethoxycarbonyl, 1-(acetoxy)ethoxycarbonyl,1-(isobutylyloxy)ethoxycarbonyl, cyclohexylcarbonyloxymethoxycarbonyl,benzoyloxymethoxycarbonyl, cinnamiloxycarbonyl andcyclopentylcarbonyloxymethoxycarbonyl, etc.. Furthermore, R² may be anyof the groups actually or potentially capable of forming an anion (e.g.,COO or its derivatives, etc.) under biologic, or physiologic, conditions(e.g., oxidation or reduction induced by an enzyme present in the livingbody; in vivo reaction such as hydrolysis) or chemically. R² may also bea carboxyl group or its prodrug. R² may be a group capable of beingbiologically or chemically biotransformed to an anion.

[0048] Among the groups described as R², preferable ones includecarboxyl, esterified carboxyl (e.g. methyl ester, ethyl ester or anester formed by binding of a group represtented by the above mentionedformula —O—CH(R⁶)—OCOR⁵ to carbonyl) and optionally protectedtetrazolyl, carboaldehyde and hydroxymethyl.

[0049] In general formula (I), ring A may have, in addition to the grouprepresented by R², another substituent, e.g., a halogen atom (e.g., F,Cl, Br, etc.), cyano group, nitro group, lower (C₁₋₄) alkyl group, lower(C₁₋₄) alkoxyl group, optionally substituted amino group {e.g., amino,N-lower (C₁₋₄) alkylamino (e.g., methylamino, etc.), N,N-dilower (C₁₋₄)alkylamino (e.g., dimethylamino, etc.), N-arylamino (e.g., phenylamino,etc.), alicyclic amino (e.g., morpholino, piperidino, piperazino,N-phenylpiperazino, etc.), etc.}, a group represented by the formula—CO-D′ [wherein D′ stands for a hydroxyl group or a lower (C₁₋₄) alkoxylgroup whose alkyl moiety may be substituted with a hydroxyl group, lower(C₁₋₄) alkoxyl group, lower (C₂₋₆) alkanoyloxy (e.g., acetoxyl,pivaloyloxyl, etc.) or lower (C₁₋₆) alkoxycarbonyloxyl (e.g.,methoxycarbonyloxyl, ethoxycarbonyloxy, cyclohexyloxycarbonyloxy, etc.)group], or tetrazolyl, trifluoromethanesulfonamide, phosphoric acid orsulfonic acid group which may be protected by lower (C₁₋₄) alkyl or acylgroup (e.g., lower (C₂₋₅) alkanoyl, optionally substituted benzoyl,etc.); among them, a lower (C₁₋₄) alkyl group and a halogen group arepreferable. Of these substituents, one or two may simultaneouslysubstitute for groups at available positions in the ring.

[0050] Among the compounds represented by the above mentioned formula(I), compounds represented by formula (I′) are preferred:

[0051] [wherein ring A stands for a benzene ring which may have another1 or 2 substituents in addition to the group represented by R²; R¹stands for H or an optionally substituted lower (C₁₋₆) alkyl (preferablylower (C₁₋₄) alkyl); Y stands for O, N(H) or S; R² is a grouprepresented by the formula —CO-D″ [wherein D″ stands for hydroxyl group,or a lower (C₁₋₄) alkoxy whose alkyl moiety is optionally substitutedwith hydroxyl group, amino, halogen, a lower (C₁₋₆) alkanoyloxy (e.g.acetyloxy and pivaloyloxy, etc.), lower (C₄₋₇) cycloalkanoyloxy, lower(C₁₋₆) alkoxycarbonyloxy (e.g. methoxycarbonyloxy, ethoxycarbonyloxy),lower (C₃₋₇) cycloalkoxycarbonyloxy (e.g. cyclohexyloxycarbonyloxy) or alower (C 14) alkoxy; R³ stands for a tetrazolyl, carboxyl group orgroups represented by the formula,

[0052] wherein i stands for —O— or —S—; j stands for >C=0, >C═S or>S(O)_(m); and m is of the same meaning as defined above, which areoptionally protected with optionally substituted lower (C₁₋₄) alkyl(e.g. methyl, triphenylmethyl, methoxymethyl, acetyloxymethyl,methoxycarbonyloxymethyl, ethoxycarbonyioxymethyl,1-(cyclohexyloxycarbonyloxy)ethyl and pivaloyloxymethyl, etc.) or anacyl group (e.g. a lower C₂₋₅ alkanoyl and benzoyl, etc.).; n is 1 or 2.

[0053] In the formula (I′), substituents on the optionally substitutedlower alkyl for R¹ include a hydroxyl group, an amino group, halogen anda lower (C₁₋₄) alkoxy group.

[0054] In the formula (I′), ring A is a benzene ring which may have asubstituent, in addition to the group R², such as a halogen (e.g., F,Cl, Br), lower (CI₄) alkyl, lower (C₁₋₄) alkoxy, nitro, a grouprepresented by the formula —CO-D′, wherein D′ represents a hydroxylgroup or a lower (C₁₋₄) alkoxy whose alkyl moiety may be substitutedwith a hydroxyl group, lower (C₁₋₄) alkoxy, lower (C₂₋₆) alkanoyloxy(e.g., acetoxy, pivaloyloxy, etc.) or lower (C₁₋₆) alkoxycarbonyloxy(e.g., methoxycarbonyloxy, ethoxycarbonyloxy, cyclohexyloxycarbonyloxy),or an amino which may be substituted with a lower (C₁₋₄) alkyl(preferably a substituent such as a lower (C₁₋₄) alkyl or halogen). Morepreferably, A is a benzene ring which has no substituent in addition tothe group represented by the formula R².

[0055] As the salt thereof, pharmaceutically acceptable salts are used,e.g., a salt with an inorganic base, organic base, inorganic acid,organic acid, or basic or acidic amino acid. Inorganic bases appropriateto form the salt include alkali metals such as sodium and potassium,alkali soil metals such as calcium and magnesium, aluminum and ammonium.Organic bases appropriate to form the salt include trimethylamine,triethylamine, pyridine, picoline, ethanolamine, jetanolamine,triethanolamine, dicyclohexylamine, and N,N′-dibenzylethylenediamine.Inorganic acids appropriate to form the salt include hydrochloric acid,hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid.Organic acids appropriate to form the salt include formic acid, aceticacid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid,maleic acid, citric acid, succinic acid, malic acid, methanesulfonicacid, benzenesulfonic acid, and p-toluenesulfonic acid. Basic aminoacids to form the salt include arginine, lysine and ornithine. Acidicamino acids to for Lthe salt include aspartic acid and glutamic acid.

[0056] As an active ingredient of the present invention, the compoundsdescribed in the Examples of Japan Provisional PublicationNo.364171/1992 and EP520423 are preferred.

[0057] The compounds represented by general formula (I) were, forinstance, disclosed in Provisional Publication Nos. 9373/1992 and364171/1992, and EP520423, and can be manufactured as described in thesepublications.

[0058] Compound (I) or salts thereof possessing angiotensin IIantagonistic action referred to in the present invention are ofsufficiently low toxicity to be used as a pharmaceutical for animals,particularly mammals (e.g., humans, dogs, rabbits, rats, mice, etc.), inthe prophylaxis or treatment of diabetic nephropathy orglomerulonephritis.

[0059] Compound (I) or salts thereof represented by general formula (I)can be administered by the oral route, non-oral route, inhalation,rectal injection, or topical administration, as pharmaceuticalconstituents or preparations (e.g., powder, granules, tablets, pills,capsules, injection, syrup, emulsion, elixir, suspension, solution,etc.). At least one compound of the present invention can be used singlyor in mixture with a carrier allowable as a pharmaceutical (adjuvant,vehicle, supportive agent, andlor diluting agent).

[0060] The constituents of a pharmaceutical can be prepared according tothe usual manner. In the present specification, the non-oral routeincludes subcutaneous injection, intravenous injection, intramuscularinjection, peritoneal injection and intravenous drip. For prescriptioninjection, sterile aqueous or oily suspensions for injection can beprepared by using an appropriate emulsifier or humidifier and asuspending agent, according to kown methods. The sterile prescriptionagent for injection may be a non-toxic, non-orally administrablediluting agent such as aquous solution or a sterile injectable solutionor suspension in a solvent. As the usable vehicle or solvent, water,Ringer's solution, isotonic saline, etc. are allowed; as an ordinarysolvent, or suspending solvent, sterile involatile oil can be used. Forthese purposes, any kind of involatile oil and fatty acid can be used,including natural or synthetic or semisynthetic fatty oils or fattyacids; natural or synthetic or semisynthtetic mono- or di- ortri-glycerides.

[0061] The suppository for rectal administration can be manufactured viaa particular process, in which the drug is mixed with an appropriate,non-irritant supporting agent, e.g., cocoa butter or polyethyleneglycol, that is solid at normal temperature but liquid at intestinaltemperature and therefore melts in the rectum to release the drug.

[0062] As the solid-type dosage form for oral administration, powder,granules, tablets, pills and capsules are listed as mentioned above. Inthese dosage forms, the active constituent compound can be mixed with atleast one additive, including sucrose, lactose, cellulose, mannitol,maltitol, dextran, starches, agar, arginates, chitins, chitosans,pectins, gum tragacanth, gum arabic, gelatin, collagen, casein, albumin,synthetic or semisynthetic polymer, and glyceride. These dosage formscan also contain other type(s) of additives, e.g., inactive dElutingagent, lubricant such as magnesium stearate, paraben, preserving agentsuch as sorbic acid, ascorbic acid, a-tocopherol, antioxidant such ascysteine, disintegrator, binder, thickener, buffering agent, sweeteningagent, flavoring agent, perfuming agent, etc. Tablets and pills can befurther processed into enteric coated preparations. The liquidpreparations for oral administration include emulsion, syrup, elixir,suspension and solution preparations allowable for medical use. Thesepreparations may contain inactive diluting agents ordinarily used insaid field, e.g., water.

[0063] The dosage for a particular patient is determined according toage, body weight, general health conditions, sex, diet, administrationtime, adininistration method, excretion rate, drug combination, andseverity of the illness being treated, in consideration of those orother factors.

[0064] The compounds and salts thereof represented by general formula(I) can be safely used at low toxicity level; the daily dose varies withpatient condition, body weight, type of compound, administration route,etc.; e.g., non-orally, i.e. for subcutaneous, intravenous,intramuscular or intrarectal use, approximately 0.01-50 mg/person/day,preferably 0.01-20 mg/person/day, and orally, approximately 0.01-150mg/person/day, preferably 0.1-100 mg/person/day, are recommended.

[0065] The invention is described in more detail with reference toexamples. However, the invention is not limited to the specificembodiments.

EXAMPLE Preparation example

[0066] The prophylactic or therapeutic drug containing compound (I) or asalt thereof, referred to in the present invention as the activeconstituent for diabetic nephropathy or glomerular nephritis, forinstance, can be manufactured according to the following formula:

[0067] 1. Capsules (1)2-ethoxy-1-[[2′-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl]-1H- 10 mgbenzimidazole-7-carboxylic acid (2) Lactose 90 mg (3) Microcrystallinecellulose 70 mg (4) Magnesium stearate 10 mg One capsule 180 mg 

[0068] After (1) is mixed with (I (3) and half of (4), the mixture isgranulated. To the granules, the other half of (4) is added; the entiremixture is then sealed in a gelatin capsule.

[0069] 2. Tablets (1)2-ethoxy-1-[[2′-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl]-1H-  10 mgbenzimidazole-7-carboxylic acid (2) Lactose  35 mg (3) Corn starch 150mg (4) Microcrystalline cellulose  30 mg (5) Magnesium stearate  5 mgOne tablet 230 mg

[0070] After (1) is mixed with (2), (3), 2/3 of (4) and half of (5), themixture is granulated. To the granules, the remaining amounts of (4) and(5) are added; the mixture is then press-shaped into a tablet.

[0071] 3. Injection (1)2-ethoxy-1-[[2′-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl]-1H-  10 mgbenzimidazole-7-carboxylic acid (2) Inositol 100 mg (3) Benzylalcohol 20 mg One ampule 130 mg

[0072] (1), (2) and (3) are dissolved in distilled water for injectionto make the total volume 2 ml; the solution is sealed in an ampule. Theentire process should be conducted under sterile conditions.

[0073] 4. Capsules (1) (±)-1-(cyclohezyloxycarbonyloxy)ethyl2-ethoxy-1-[[2′-(1H- 10 mgtetrazole-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7- carboxylate (2)Lactose 90 mg (3) Microcrystalline cellulose 70 mg (4) Magnesiumstearate 10 mg One capsule 180 mg 

[0074] After (1) is mixed with (2), (3) and half of (4), the mixture isgranulated. To the granules, the other half of (4) is added; the entiremixture is then sealed in a gelatin capsule.

[0075] 5. Tablets (1) (±)-1-(cyclohezyloxycarbonyloxy)ethyl2-ethoxy-1-[[2′-(1H- 10 mgtetrazole-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7- carboxylate (2)Lactose 35 mg (3) Corn starch 150 mg  (4) Microcrystalline cellulose 30mg (5) Magnesium stearate  5 mg One tablet 230 mg 

[0076] After (1) is mixed with (2), (3), 2/3 of (4), and half of (5),the mixture is granulated. To the granules, the remaining amounts of (4)and (5) are added; the entire mixture is then press-shaped into atablet.

[0077] 6. Injection (1)2-ethoxy-1-[[2′-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl]-1H-  10 mgbenzimidazole-7-carboxylic acid disodium salt (2) Inositol 100 mg (3)Benzylalcohol  20 mg One ampule 130 mg

[0078] (1), (2) and (3) are dissolved in distilled water for injectionto make the total volume 2 ml; the solution is then sealed in an ampule.The entire process should be conducted under sterile conditions.

[0079] 7. Capsules (1)2-ethoxy-1-[[2′-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl]-1H- 10 mgbenzimidazole-7-carboxylic acid (2) Lactose 90 mg (3) Microcrystallinecellulose 70 mg (4) Magnesium stearate 10 mg One capsule 180 mg 

[0080] After (1) is mixed with (2), (3) and half of (4), the mixture isgranulated. To the granules, the other half of (4) is added; the entiremixture is then sealed in a gelatin capsule.

[0081] 8. Tablets (1)2-ethoxy-1-[[2′-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl]-1H-  10 mgbenzimidazole-7-carboxylic acid (2) Lactose  35 mg (3) Corn starch 150mg (4) Microcrystalline cellulose  30 mg (5) Magnesium stearate  5 mgOne tablet 230 mg

[0082] After (1) is mixed with (2), (3), 2/3 of (4) and half of (5), themixture is granulated. To the granules, the remaining amounts of (4) and(5) are added; the mixture is then press-shaped into a tablet.

[0083] 9. Capsules (1) Pivaloyloxymethyl2-butyl-1-[[2′-(1H-tetrazole-5-yl)biphenyl-4- 10 mgyl]methyl]-1H-benzimidazole-7-carboxylate (2) Lactose 90 mg (3)Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg Onecapsule 180 mg 

[0084] After (1) is mixed with (2), (3) and half of (4), the mixture isgranulated. To the granules, the other half of (4) is added; the entiremixture is then sealed in a gelatin capsule.

[0085] 10. Tablets (1) Pivaloyloxymethyl2-butyl-1-[[2′-(1H-tetrazole-5-yl)biphenyl-4- 10 mgyl]methyl]-1H-benzimidazole-7-carboxylate (2) Lactose 35 mg (3) Cornstarch 150 mg  (3) Microcrystalline cellulose 30 mg (4) Magnesiumstearate  5 mg Total 230 mg per tablet

[0086] Components (1), (2), (3), a two-thirds portion of component (4)and a 0 half portion of componen t(5) were mixed and granulated. Tothese granules, the remaining portions of components (4) and (5) wereadded, and the whole mixture tableted by compressive tableting.

[0087] 11. Capsules (1)2-ethoxy-1-[[2′-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)  10 mgbiphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (2) Lactose  90mg (3) Microcrystalline cellulose  70 mg (4) Magnesium stearate  10 mgOne capsule 180 mg

[0088] 12. Tablets (1)2-ethoxy-1-[[2′-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)  10 mgbiphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (2) Lactose  35mg (3) Corn starch 150 mg (4) Microcrystalline cellulose  30 mg (5)Magnesium stearate  5 mg One tablet 230 mg

[0089] After (1) is mixed with (2), (3), 2/3 of (4) and half of (5), themixture is granulated. To the granules, the remaining amounts of (4) and(5) are added; the mixture is then press-shaped into a tablet.

[0090] The biologic activity of compounds and salts thereof possessingangiotensin-II-antagonistic action are described in Test Examples.

Test Example 1

[0091] Antiproteinuric action in rats with subtotally (5/6) nephrectomy(focal glomerulorsclerosis model; Meyer, T. W. and Renake, H. G.: Am. J.Physiol. 254, F856 (1988) or Yoshioka, T., Shiraga, H., Yoshida, Y.,Fogo. A., Glick, A. D.: J. Clin. Invest. 82, 1614 (1988)) Compound 1:(±)-1-(cyclohexyloxycarbonyloxy)ethyl2-ethoxy-1-[[2′-(1H-tetrazole-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylateMethod: Five-week-old male rats were anesthetized by intraperitonealinjection of pentobarbitasodium and 2/3 of the right kidney was removed.One week later, the entire left kidney was removed under similaranesthesia. After two-week breeding, 24-hour urine was collected and thetotal protein content and albumin content in the urine were determinedby the use of A/G-B test (Wako Pure Chemistry Co., Ltd.). On the basisof urinary protein and blood pressure (BP), the rats were divided intotwo groups (vehicle-treated rats and rats treated with 1 mg/kg/day, p.o.of compound 1). Rats undergoing nephrectomy of the left kidney alonewere also used as sham operated rats. Compound 1 was suspended ingum-arabic and the suspension was orally iadministered once a day foreight weeks. At the 2nd, 4th, 6th and 8th week of the treatment, 24-hoururine was collected. Results: Table 1 summarizes the results. Urinarytotal protein and albumin began to markedly increase in vehicle-treatedrats two weeks after surgery. Whereas, in rats treated with compound 1,these parameters did not increase and each parameter was rathersignificantly low six to eight weeks after the beginning ofadministration as compared with vehicle-treated rats. Since compound 1suppresses aggravation of renal impairment, its efficacy inglomerulonephritis or diabetic nephropathy is expected. TABLE 1Antiproteinuric Action in subtotally (5/6) nephrectomized Rats 2 weeks 4weeks 6 weeks Preadminist- after the after the after the 8 weeks afterration first dose first dose first dose the first dose Urinary Vehicle33.1 ± 3.1  36.4 ± 5.2 39.4 ± 4.8  35.3 ± 6.1  55.1 ± 9.1 total (n =8-9) protein Com- 32.8 ± 5.4  30.9 ± 5.2 27.7 ± 4.0  17.6 ± 5.6* 24.4 ±2.7** (mg/100 g/ pound 1 24 hr) (n = 9) Shams 9.7 ± 0.7 14.9 ± 1.5 13.1± 1.4  8.3 ± 0.5 11.9 ± 1.3 (n = 6) Urinary Vehicle 7.7 ± 2.6 12.0 ± 3.114.1 ± 3.0 15.1 ± 3.7  24.5 ± 7.1 albumin (n = 8-9) (mg/100 g/ Com- 7.3± 2.3  6.3 ± 2.9  6.8 ± 3.4*  7.4 ± 4.0*  5.6 ± 2.7** 24 hr) pound 1 (n= 9) Shams 2.1 ± 0.2  1.9 ± 0.2 2.1 ± 0.2 1.3 ± 0.2  1.6 ± 0.2 (n = 6)

Test Example 2

[0092] Antiproteinuric action in rats with non-insulin-dependent (NIDD)diabetes (Wistar fatty rats) (Ikeda, H., Shino, A., Matsuo, T.,Iwatsuka, H., and Suzuoki, Z.: Diabetes, 30, 1045 (1981) or Kava, R. A.,West, D. B., Lukasik, V. A., and Greenwood, M. R. C: Diabetes, 38,159(1989) Compound 1: (±)-1-(cyclohexyloxycarbonyloxy)ethyl2-ethoxy-1-,[[2′-(1H-tetrazole-5-yl)biphenyl-4yl]methyl]-1H-benzicidazole-7-carboxylateMethod: On the basis of blood glucose level and urinary protein content,11-week-old Wistar fatty rats were divided into two groups(vehicle-treated rats and rats treated with 1 mg/kg/day, p.o. ofcompound 1). Non-diabetic control rats (lean rats) were also used.Compound 1 was suspended in gum-arabic and the suspension was orallyadministered once a day for ten weeks. At the 2nd, 4th, 6th, 8th and10th week of the treatment, 24-hour urine was collected. The urine wascentrifuged at 3,000 rpm and a portion of the supernatant was desaltedon a column (Pharmacia PD10). Urinary total protein content and albumincontent were determined by Lowry and ELISA methods, respectively.Results: Table 2 summarizes the results. Urinary total protein contentincreased in vehicle-treated rats to about three times of the value inlean rats. This increase, however, was reduced to 1.2-1.5 times bythe-treatment with compound 1. Urinary albumin content also increased invehicle-treated rats to about 100 times of the value in lean rats. Thisincrease, however, was reduced to 20-30 times by the treatment withcompound 1. Compound 1 did not affect blood glucoselevel. Innon-insulin-dependent diabetic models, compound 1 is expected to beeffective against diabetic nephropathy by decreasing the urinary proteinwithout affecting the blood glucose level. TABLE 2 AntiproteinuricAction in Rats with non-insulin-dependent diabetes age 11 weeks 13 weeks15 weeks 17 weeks 19 weeks 21 weeks Urinary vehicle 101 ± 5 94 ± 14 118± 16 135 ± 15 117 ± 15 143 ± 22 total (n = 6) protein Com- 101 ± 6 69 ±11  91 ± 12  97 ± 11*  79 ± 10*  74 ± 13* (mg/24 hr) pound 1 (n = 6)Lean  55 ± 2 36 ± 3  51 ± 3  51 ± 3  45 ± 2  45 ± 2 (n = 6) Urinaryvehicle 2.9 ± 24.6 ± 42.7 ± 46.4 ± 38.6 ± 28.6 ± albumin (n = 6) 0.4 7.59.0 10.4 6.4 5.2 (mg/24 hr) Com- 6.5 ± 11.2 ± 14.8 ± 21.8 ± 10.7 ± 15.4± pound 1 4.1 3.9 6.1* 8.2 3.9* 3.7* (n = 6) Lean 0.4 ±  0.4 ±  0.6 ± 0.7 ±  0.6 ±  0.4 ± (n = 6) 0.02 0.04 0.05 0.08 0.04 0.03

[0093] Values are expressed as mean ± standard error. Figures inparentheses denote the number of rats. Significance difference testingbetween controls and compound-1-treated orlean rats: *P <0.05.

Test Example 3

[0094] Acute Toxicity Test

[0095] Compound 1: (±)-1-(cyclohexyloxycarbonyloxy)ethyl2-ethoxy-1-[[2′-(1H-tetrazole-5-yl)biphenyl-4yl]methyl]-1H-benrmidazole-7-carboxylateThe LD₅₀ of compound 1 is 2,000 mgfkg or more for 4week-old Jcl:ICR mice(males and females) and for 5-week-old Jcl:Wister rats (males andfemales) via single oral administration.

What is claimed is:
 1. A method for the prophylaxis or treatment ofdiabetic nephropathy or glomerulonephritis in a mammal comprising thestep of administering a pharmaceutically effective amount of a compoundor salt thereof represented by formula (I)

wherein R¹ stands for H or an optionally substituted hydrocarbonresidue; R² stands for an optionally esterified carboxyl group; R³stands for a group capable of forming an anion; X shows that thephenylene and phenyl groups bond to each other directly or through aspacer having an atomic chain length of two or less; n stands for 1 or2; ring A stands for a benzene ring having 1 or 2 optional substituentsin addition to R²; Y stands for a bond, —O—, —S(O)_(m)— wherein m standsfor 0, 1 or 2, or —N(R⁴)— wherein R⁴ stands for H or an optionallysubstituted alkyl group, to a mnanmal in need thereof.
 2. The method ofclaim 1 wherein R¹ stands for a lower alkyl or lower cycloalkyl groupwhich may be substituted.
 3. The method of claim 2 wherein R¹ stands forethyl.
 4. The method of claim 1 wherein R¹ stands for ethyl and Y standsfor —O—.
 5. The method of claim 1 wherein R² stands for a grouprepresented by the formula —CO-D″ wherein D″ stands for hydroxyl, orlower (C₀₁₄) alkoxy whose alkyl moiety is optionally substituted withhydroxyl, amino, halogen, lower (C₂₋₆) alkanoyloxy, lower (C₄₋₇)cycloalkanoyloxy, lower (C₁₋₆) alkoxycarbonyloxy, lower (C₃₋₇)cycloalkoxycarbonyloxy or lower (C₁₋₄) alkoxy.
 6. The method of claim 5wherein R² stands for a lower alkoxycarbonyl group substituted withcyclohexyloxycarbonyloxy.
 7. The method of claim 1 wherein R³ is anoptionally substituted 5-7 membered monocyclic heterocyclic residuehaving a hydrogen atom capable of leaving as a proton.
 8. The method ofclaim 7 wherein R³ stands for one of the following.


9. The method of claim 8 wherein R³ stands for tetrazolyl.
 10. Themethod of claim 1 wherein R² stands for a lower alkoxylcarbonyl groupsubstituted with an cyclohexyloxycarbonyloxyl group and R³ stands for atetrazolyl group.
 11. The method of claim 1 wherein R¹ stands for alower alkyl group; Y stands for —O—; R² stands for a loweralkoxycarbonyl group substituted with a cyclohezyloxycarbonyloxyl group;and R³ stands for a tetrazolyl group.
 12. The method of claim 1 whereinsaid compound represented by formula (I) is(±)-1-(cyclohexyloxycarbonyloxy)ethyl2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate.13. The method of claim 1 wherein said compound represented by formula(I) is2-ethoxy-1-[[2′-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl]-1H-benzoimidazole-7-carboxylicacid.
 14. The method of claim 1 -wherein said compound represented byformula (I) is pivaloyloxymethyl²-ethoxy-1-[[2′-(1H-tetrazole-5-yl)biphenyl-4yl]methyl]-1H-benzimidazole-7-carboxylate.15. The method of claim 1 wherein said compound represented by formula(I) is2-ethoxy-1-[[2′-(4,5-dihydro-5-oxo-1,2,4-oxadiazole-3-yl)biphenyl-4yl]methyl]-1H-benzimidazole-7-carboxylicacid.